Sindrome di Alport (ATS) nefropatia ereditaria progressiva

eterogenea dal punto vista clinico e genetico

CRITERI CLINICI

Storia familiare positiva per ematuria o insufficienzarenale cronica (IRC)

Alterazioni ultrastrutturali della membrana basale glomerulare (GMB)

Anomalie oculari (lenticono, macchie perimaculari, erosioni corneali ricorrenti)

Ipoacusia neurosensoriale per le alte frequenze

0.3-2.6% pazienti che sviluppano ESRD in Europa

Sindrome di Alport (ATS)-malattia delle membrane basali

(del collagene di tipo IV)

•X-legata (circa il 90% dei casi) – gene COL4A5

•autosomica recessiva – geni COL4A3 e COL4A4

•autosomica dominante – geni COL4A3 e COL4A4

Gubler MC (2008) Inherited diseases of the glomerular basement membraneNat Clin Pract Nephrol 4: 24–37, 2007

Kalluri R. Nature Reviews, 2003

Kalluri R. Nature Reviews, 2003

Gubler MC (2008) Inherited diseases of the glomerular basement membraneNat Clin Pract Nephrol 4: 24–37, 2007

Gubler MC (2008) Inherited diseases of the glomerular basement membraneNat Clin Pract Nephrol 4: 24–37, 2007

Figure 5 Immunohistological analysis of the distribution of the

α5(IV) collagen chain

ATS ARcontrollo Maschio ATS XL Femmina ATS XL

Gubler MC (2008) Inherited diseases of the glomerular basement membraneNat Clin Pract Nephrol 4: 24–37, 2007

I

II

III

64aa IRC lieve

ESRD a 33aa

ipoacusia

ESRD a 18aa

ipoacusia

ESRD a 22aa

ipoacusia

Microematuria intermittente

Jais JP et al, J Am SocNephrol. 2000 Apr;11(4):649-57.

Jais JP et al, J Am Soc Nephrol.2003 Oct;14(10):2603-10.

Jais JP et al, J Am Soc Nephrol.2003 Oct;14(10):2603-10.

3209insA w

3386del27 w

3209insA 3386del273209insA 3386del27ww

COL4A317 y

Microhematuria

macrohematuria

CRF (creatininemia 2 mg%)

Bilateral mixed hearing loss

Delayed growth

9 y

Microhematuria

macrohematuria

Creatinininemia 0,4 mg%

43 y

Microhematuria

Macrohematuria

Creatininemia 0,9 mg%

AUTOSOMAL RECESSIVE ALPORT SYNDROME

Longo I, et al. Nephrol Dial Transplant 2006;21(3):665-71.

40del24 w ww

40del24 w

COL4A3

14 y

Microhematuria

Mild proteinuria

Normal renal function

46 y

Microhematuria

Macrohematuria

High tone hypoacusia

AUTOSOMAL DOMINANT ALPORT SYNDROME

Longo I et al., Kidney Int. 2002 Jun;61(6):1947-56Pescucci C. et al. Kidney Int. 2004;65(5):1598-603

54 y

CRF

88 y death

Dialysis since the age of 84

Bilateral neurosensory hearing loss

67 y

Microhematuria

proteinuria

CRF (creatininemia 1,4mg%)

Bilateral neurosensory

hearing loss

G1045Vw

43-20 y

Microhematuria

COL4A3

G1045Vw

AUTOSOMAL DOMINANT ALPORT SYNDROME

Pescucci C, et al. Kidney Int. 2004;65(5):1598-603.

II

III

I90 aa

non penetrante+/-

+/- -/-+/- -/--/-

+/- -/-

p.C1634SCOL4A4

Pescucci C, et al. Kidney Int. 2004;65(5):1598-603.

Marcocci E, et al. Nephrol Dial Transplant. 2009;24(5):1464-71.

Marcocci E, et al. Nephrol Dial Transplant. 2009;24(5):1464-71.

Microematuria dall’età di 48 anni (creatininemia1.4 mg%)

31 anniMicroematuria Normale funzione renale

Trapianto renaleall’età di 52 anni

Arriva dallo specialista nefrologocon diagnosi di sindromedi Alport X-legato erichiesta di analisi del gene COL4A5

Dopo la consulenza genetica

si decide di analizzare i geni COL4A3-4invece del gene COL4A5

Mutazione nel gene COL4A4 e

diagnosi di sindrome di Alport

autosomico dominante

family GST

G1198S w

COL4A3

39 y

Microhematuria

Proteinuria

Normal renal function

AUTOSOMAL DOMINANT ALPORT SYNDROME, or BFH ?

Longo I. et al, Kidney Int. 2002 Jun;61(6):1947-56.

COL4A5 heterozygous female

CRF

COL4A5 hemizygous male

Non sympthomaticcarrier

Microhematuria CRF

Only 15%

COL4A3/4 homozygous, male/female

AutosomalRecessiveAlport syndrome

COL4A3/4 heterozygous, male/female

Non sympthomaticcarrier

BenignFamilialHematuria

AutosomalDominantAlport syndrome